Cancer is the second leading cause of death after heart disease in the United State (Cancer Facts and FIGS. 2005, American Cancer Society, Inc.). In the early stage of cancer development, a method of removing tumors or killing cancer cells by chemotherapy, radiotherapy, and the like may be selected, but in the case of terminal cancer patients, side effects due to aggressive therapies are relatively large and the response rate after treatment is low, and thus therapies for reducing side effects by delaying cancer progression and improving the quality of life may be selected. In these aspects, anticancer drugs are intended to not only prevent cancer recurrence by destroying cancer cells, but also prolong the survival period by inhibiting the growth and proliferation of cancer cells, when it is difficult to expect a full recovery.
Existing chemotherapy for metastatic cancers fail to provide long-term treatment due to their reduced efficacy. In addition, although new chemotherapies have been introduced in the medical field, there is still a need for novel effective medicines as primary, secondary and tertiary therapies in single treatment or co-treatment with existing agents, for the treatment of resistant tumors.
In addition, even anticancer drugs with strong potency are not applicable to all cancers, and thus there is an urgent need to develop medicines to improve treatment efficiency.
Targeted therapies are advantageous in that they are tumor-specific, effective, and have far less effect on normal cells compared to existing systemic anticancer treatments. The dysregulation of protein kinases is commonly found in cancer cells, and thus is an attractive target for the development of anticancer drugs.
Among lipid kinases, the structure and function of PI3Ks (phosphatidylinositol-3-kinase isomers) have been gradually and clearly verified in recent years. PI3Ks are known to belong to a family of enzymes that play a vital role in intracellular signaling pathways and are involved in major cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking.
Over the past 20 years, it has been steadily revealed that when PI3Ks lose their regulatory function, problems such as overactivation and the like occur in intracellular signaling pathways to induce many types of diseases.
PI3Ks are classified into Class I, Class II, and Class III. Class I is divided again into sub-classes: Class IA and Class IB. Class I PI3K is in the form of a dimer, and the dimer is divided into catalytic and regulatory subunits. Class 1A PI3K is a dimer consisting of a p110 catalytic subunit and a p85 regulatory subunit, and in this regard, the p110 catalytic subunit includes three isoforms, i.e., p110α, p110β, and p110δ. Thus, the isoforms of PI3Ks are referred to as PI3Kα, PI3Kβ, and PI3Kδ.
Meanwhile, Class IB PI3K is a dimer consisting of a p110γ catalytic subunit and a p101 regulatory subunit, and the PI3K is generally referred to as PI3Kγ.
PI3Kδ is mainly induced by receptor tyrosine kinases (RTKs) to phosphorylate PIP2 to PIP3, and PI3Kγ is mainly induced by G-protein coupled receptors (GPCRs) to phosphorylate PIP2 to PIP3. PIP3 activates protein kinase B (Akt/PKB) and continuously leads to downstream signaling, thereby being involved in major cell function regulation such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. It has been one of the strongest concerns of recent years that various diseases ranging from inflammation and autoimmunity to hematologic malignancy and solid cancer occur when PI3Kδ and PI3Kγ have malfunction in the regulation of intracellular signal transduction, and accordingly, there have been intensive efforts to develop drugs for treating inflammation, autoimmunity, hematologic malignancy, and solid cancer by inhibiting PI3Kδ and PI3Kγ that lose their regulatory functions.
An example of representative drugs being developed in this field is idelalisib, a substance that was developed by Gilead Calistoga and selectively inhibits PI3Kδ. This drug has excellent efficacy against various types of hematologic malignancies, and thus has drawn attention as a breakthrough drug that addresses problems (especially cytotoxicity against normal cells) of existing cytotoxic anticancer drugs and also compensates for problems of the efficacy of existing anticancer drugs. However, in Europe, some cases of serious toxicity has occurred during clinical trials, in which patients died from pneumonia, and thus the development of this drug has now been suspended. According to a report, the reason is that the inhibitory activity of this drug was sufficiently selective and potent for PI3Kδ rather than for PI3Kα and PI3Kβ, but not sufficiently selective than for PI3Kγ. Duvelisib exhibited dual-inhibitory activity on PI3Kδ and PI3Kγ and thus had a possibility of being developed as a very promising drug for treating hematologic malignancy, inflammation, and autoimmune disease. However, during clinical trials, the development of Duvelisib was terminated because of problems similar to those of idelalisib. It is known that the inhibitory efficacy of this substance is not sufficiently selective for PI3Kδ and PI3Kγ than for PI3Kβ. Therefore, there is a need to develop a drug capable of more selectively inhibiting PI3Kδ rather than at least idelalisib.
Meanwhile, quinazolinone derivatives are special structures present in many biologically active compounds such as methaqualone, which is a sedative-hypnotic drug, chloroqualone, which is an antitussive, and piriqualone, which is an anticonvulsant. Quinazolinone and derivatives thereof have a wide range of biological properties such as hypnosis, pain killing, inhibition of convulsions, inhibition of coughing, and anti-inflammatory activity.
In particular, quinazolinone derivatives are used in the treatment of cell proliferative diseases including cancer, and are one of the therapeutic agents which have been widely used recently. For example, U.S. Pat. Nos. 5,747,498 and 5,773,476 disclose quinazolinone derivatives used for the treatment of cancer which is induced by over-activation or aberrant activation of receptor tyrosine kinases. Therefore, quinazolinone derivatives are required to be studied and developed through various approaches for the treatment of cell proliferative diseases.